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The Role of Lipid Rafts in Fetal Alcohol Spectrum Disorder

脂筏在胎儿酒精谱系障碍中的作用

基本信息

批准号：
8066801
负责人：
CYNTHIA FRANCES BEARER
金额：
$ 28.55万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066801
关键词：
Acids Alcohol-related birth defects Alcohols Animals Behavioral Brain Cell membrane Cells Cholesterol Choline Cysteine Cytoplasmic Granules Data Defect Development Developmental Neurotoxicity of Ethanol Dietary Intervention Endocytosis Ethanol Ethanol toxicity Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Folic Acid Ganglioside GM1 Growth Cones Heavy Drinking Homing Human In Vitro Incidence Infant Intervention Kinetics Live Birth MAPK3 gene Measures Mediating Membrane Microdomains Mental Retardation Modeling Mus NAPVSIPQ peptide Nervous system structure Neural Cell Adhesion Molecule L1 Neural Tube Defects Neuraxis Neurites Neurons Newborn Infant Nutrient Outcome Pathway interactions Peripheral Pregnancy Protective Agents Proteins Psychological Tests Public Health Rattus Recycling Research Research Personnel Role Secondary to Signal Transduction Site Supplementation System Teratogens Test Result Testing Toxic effect Trefoil Motif Work alcohol effect alcohol exposure alcohol sensitivity base cost drinking in vivo in vivo Model mutant nervous system development neurofascin neurotoxicity prevent programs protein distribution protein protein interaction pup trafficking

项目摘要

DESCRIPTION (provided by applicant): Ethanol is a known human teratogen of immense public health impact. Heavy drinking during pregnancy is the leading known cause of mental retardation, while more subtle effects particularly on the developing brain occur in 1% of all liveborns. Recent evidence has shown that many of the known protein targets for ethanol's toxic effects on the developing central nervous system are associated with lipid rafts. Lipid rafts are specialized microdomains of the plasma membrane and serve as platforms for protein-protein interactions. Our prior work has shown that the ability of L1 cell adhesion molecule (L1), a protein critical for the proper development of the nervous system, to promote neurite outgrowth is exquisitely sensitive to ethanol. Localized disruption of lipid rafts reduces L1 mediated neurite outgrowth. Our preliminary data show that ethanol alters the distribution of L1 in lipid rafts, and that cholesterol depletion abolishes ethanol sensitivity. Further, our preliminary data suggests that other protein targets of ethanol change their lipid raft distribution in the presence of ethanol. We hypothesize that a major mechanism of ethanol toxicity is through alteration of lipid raft-protein interactions, and that interventions which reduce toxicity prevent this disruption. These hypotheses will be tested using cerebellar granule neurons (CGN) from rat pups and from mice, both wild type and lacking L1, and a rat in vivo entubation model. In Aim 1, we will confirm that lipid raft-L1 interactions underlie ethanol sensitivity of neurite outgrowth by transfecting CGN lacking L1 with mutant constructs of L1 lacking a signal to colocalize with lipid rafts. Neurite outgrowth in transfected cells is expected to be ethanol insensitive. In Aim 2, we will determine whether L1 or the lipid raft is the site of the ethanol action, and the effect of ethanol on the kinetics of L1 trafficking to and out of the lipid raft compartment. In Aim 3, we will use four nutrients shown to be protective in other experimental systems, to prevent the changes in protein distribution secondary to ethanol. The most effective combination of these nutrients will be determined with L1 in CGN and in the in vivo model. The relevance of this research is that simple dietary manipulations with these nutrients may prevent some aspects of ethanol neurotoxicity much like folic acid supplementation and reduction of neural tube defects.

描述（由申请人提供）：乙醇是一种已知的人类致畸剂，对公共健康影响巨大。怀孕期间大量饮酒是导致智力低下的主要原因，而 1% 的活产婴儿会受到更微妙的影响，尤其是对发育中的大脑的影响。最近的证据表明，许多已知的乙醇对发育中的中枢神经系统产生毒性作用的蛋白质靶点都与脂筏有关。脂筏是质膜的特殊微域，充当蛋白质-蛋白质相互作用的平台。我们之前的工作表明，L1 细胞粘附分子 (L1)（一种对神经系统正常发育至关重要的蛋白质）促进神经突生长的能力对乙醇极其敏感。脂筏的局部破坏减少了 L1 介导的神经突生长。我们的初步数据表明，乙醇改变了脂筏中 L1 的分布，并且胆固醇消耗消除了乙醇敏感性。此外，我们的初步数据表明，乙醇的其他蛋白质靶标在乙醇存在下会改变其脂筏分布。我们假设乙醇毒性的主要机制是通过改变脂筏-蛋白质相互作用，并且减少毒性的干预措施可以防止这种破坏。这些假设将使用来自野生型和缺乏 L1 的大鼠幼崽和小鼠的小脑颗粒神经元 (CGN) 以及大鼠体内插管模型进行测试。在目标 1 中，我们将通过用缺乏与脂筏共定位信号的 L1 突变构建体转染缺乏 L1 的 CGN，确认脂筏-L1 相互作用是神经突生长的乙醇敏感性的基础。转染细胞中的神经突生长预计对乙醇不敏感。在目标 2 中，我们将确定 L1 还是脂筏是乙醇作用的位点，以及乙醇对 L1 进出脂筏隔室的动力学的影响。在目标 3 中，我们将使用在其他实验系统中显示出保护作用的四种营养素，以防止继发于乙醇的蛋白质分布变化。这些营养素的最有效组合将由 CGN 和体内模型中的 L1 确定。这项研究的相关性在于，对这些营养素进行简单的饮食控制可以预防乙醇神经毒性的某些方面，就像补充叶酸和减少神经管缺陷一样。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Choline partially prevents the impact of ethanol on the lipid raft dependent functions of l1 cell adhesion molecule.

胆碱部分阻止乙醇对 l1 细胞粘附分子的脂筏依赖性功能的影响。

DOI：
10.1111/acer.12554
发表时间：
2014
期刊：
Alcoholism, clinical and experimental research
影响因子：
0
作者：
Tang,Ningfeng;Bamford,Penny;Jones,Jace;He,Min;Kane,MaureenA;Mooney,SandraM;Bearer,CynthiaF
通讯作者：
Bearer,CynthiaF

Ethanol causes the redistribution of L1 cell adhesion molecule in lipid rafts.

乙醇导致 L1 细胞粘附分子在脂筏中重新分布。

DOI：
10.1111/j.1471-4159.2011.07467.x
发表时间：
2011
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Tang,Ningfeng;Farah,Benjamin;He,Min;Fox,Stephanie;Malouf,Alfred;Littner,Yoav;Bearer,CynthiaF
通讯作者：
Bearer,CynthiaF

Bilirubin inhibits lipid raft dependent functions of L1 cell adhesion molecule in rat pup cerebellar granule neurons.

DOI：
10.1038/s41390-020-01156-0
发表时间：
2021-05
期刊：
PEDIATRIC RESEARCH
影响因子：
3.6
作者：
Kitchen, Spencer T.;Tang, Ningfeng;He, Min;Ly, Eric;Mooney, Sandra M.;Bearer, Cynthia F.
通讯作者：
Bearer, Cynthia F.

Environmental health reform in a synthetic world.

合成世界中的环境卫生改革。